Assembling defenses against therapy-resistant leukemic stem cells: Bcl6 joins the ranks

The resistance of leukemic stem cells in response to targeted therapies such as tyrosine kinase inhibitors (TKIs) relies on the cooperative activity of multiple signaling pathways and molecules, including TGFβ, AKT, and FOXO transcription factors (TFs). B cell lymphoma 6 (BCL6) is a transcriptional repressor whose translocation or mutation is associated with diffuse large BCL. New data now show that BCL6 is critical for the maintenance of leukemias driven by the BCR-ABL translocation (Philadelphia chromosome), suggesting that BCL6 is a novel, targetable member of the complex signaling pathways critical for leukemic stem cell survival

Izdvajanje i identifikacija mikroflore iz kravljeg kolostruma tradicionalnim i molekularnim metodama

Colostrum is the first milk produced by the mammary gland during the early postpartum period. In addition to nutrients, antimicrobial and growth factors, bovine colostrum contains valuable microflora, including members of the genera Lactobacillus and Bifidobacterium, which have been used widely in probiotic food. The aim of this work is to identify and quantify the microflora of colostrum samples from two Holstein dairy cows on the first three postpartum days through culture-dependent 16S rRNA gene sequencing and length heterogeneity polymerase chain reaction (LH-PCR) techniques, using an adapted method to extract the total DNA. Twenty-nine strains isolated in synthetic media were identified by their 16S rRNA gene sequences, revealing two potential probiotic strains (Lactobacillus casei and Bifidobacterium pseudolongum). Colostrum samples were subjected to LH-PCR analysis to obtain fingerprint profiles of the microflora. Lactobacillus casei was the main species present in the samples. The probiotic potential of these bacteria for use in fermented and functional foods remains to be evaluated.Kolostrum je prvo mlijeko, koje proizvodi mliječna žlijezda tijekom ranog postpartalnog razdoblja. Osim što sadrži hranjiva, antimikrobne tvari i hormone rasta, kravlji kolostrum sadržava dragocjenu mikrofloru, uključujući sojeve rodova Lactobacillus i Bifidobacterium što se koriste u proizvodnji probiotičke hrane. Svrha je ovoga rada bila identificirati i kvantificirati mikrofloru u uzorcima kolostruma dvaju Holstein mlječnih krava, uzetih tijekom prva tri dana postpartalnog razdoblja. Mikroorganizmi su određeni sekvenciranjem 16S rRNK gena i LH-PCR metodom kojom se ekstrahira ukupna DNK. U sintetičkoj je podlozi izolirano dvadeset i devet sojeva, identificiranih pomoću sekvencija 16S rRNK gena, te su izdvojena dva potencijalno probiotička soja (Lactobacillus casei i Bifidobacterium pseudolongum). Uzorci su kolostruma analizirani LH-PCR metodom kako bi se utvrdio DNK profil mikroflore, te je utvrđeno da u uzorcima prevladava vrsta Lactobacillus casei. Probiotička svojstva ove bakterije za proizvodnju fermentiranih i probiotičkih proizvoda tek treba istražiti

A 5-year retrospective study of demographic, anamnestic, and clinical factors related to psychiatric hospitalizations of adolescent patients

Background: Psychiatric emergencies of children and adolescents have greatly increased during the last years, but this phenomenon has not been studied in detail. The aim of this study was to analyze the correlation between acute psychiatric hospitalizations of adolescents and selected variables to highlight risk factors for psychiatric emergencies. Methods: This retrospective research was conducted in the acute psychiatric public ward, Service of Psychiatric Diagnosis and Treatment (SPDT), and in the residential facility for adolescents, “The Medlar”, located in Modena. The sample was constituted by all adolescent patients (n=101, age range 14–18) who had acute hospitalizations (n=140) in SPDT and had been successively transferred to “The Medlar” (n=83), from February 2, 2010 to January 31, 2015. From clinical charts, we extracted demographic and anamnestic characteristics of patients and clinical variables related to hospitalizations. Data were statistically analyzed. Results: Sixty-one percent of our patients lived with one divorced parent, with adoptive or immigrant family, or in institutions; 51% had experienced stressful events during childhood; 81% had a normal intellective level, but only 6% presented regular school performance. Parental psychiatric illness was negatively related, in a statistically significantly way, with onset age of adolescent mental disorders (coefficient -2.28, 95% confidence interval [CI]: -3.53 to 1.01, P<0.001, single linear regression; odds ratio: 4.39, 95% CI: 1.43–13.47, P<0.010, single logistic regression). The most frequent reasons for admission were aggressive behavior in males and suicide risk in females (P=0.002). The most frequent psychiatric diagnosis at SPDT discharge was “conduct disorder”, more frequent in males, followed by “adjustment disorder”, more frequent in females (P=0.001). In SPDT, the adolescent hospitalizations progressively increased fivefold at the end of the observation period. Conclusion: Our results overlap the worldwide trend of increasing adolescent psychiatric hospitalizations, suggest risk factors like parental psychiatric illness and early life stressful events, and highlight the different prevalence of aggressiveness and suicide in males and females

A 64-Channel 965-μW Neural Recording SoC with UWB Wireless Transmission in 130-nm CMOS

This brief presents a 64-channel neural recording system-on-chip (SoC) with a 20-Mb/s wireless telemetry. Each channel of the analog front end consists of a low-noise bandpass amplifier, featuring a noise efficiency factor of 3.11 with an input-referred noise of 5.6 μVrms in a 0.001- to 10-kHz band and a 31.25-kSps 6-fJ/conversion-step 10-bit SAR analog-to-digital converter. The recorded signals are multiplexed in the digital domain and transmitted via an 11.7% efficiency pulse-position modulation ultrawideband transmitter, reaching a transmission range in excess of 7.5 m. The chip has been fabricated in a 130-nm CMOS process, measures 25 mm2, and dissipates 965 μW from a 0.5-V supply. This SoC features the lowest power per channel (15 μW) and the lowest energy per bit (48.2 pJ) among state-of-the-art wireless neural recording systems with a number of channels larger than 32. The proposed circuit is able to transmit the raw neural signal in a large bandwidth (up to 10 kHz) without performing any data compression or losing vital information, such as local field potentials

Elucidating the role of the tumor suppressor Protein Phoshatase 2A in Chronic Myeloid Leukemia.

Protein phosphatase-2A (PP2A) is one of the major cellular serine-threonine phosphatases and is involved in the regulation of cell homeostasis through the negative regulation of signaling pathways initiated by protein kinases. As several cancers are characterized by the aberrant activity of oncogenic kinases, it was not surprising that a phosphatase like PP2A has progressively been considered as a potential tumor suppressor. Indeed, multiple solid tumors (e.g. melanomas, colorectal carcinomas, lung and breast cancers) present with genetic and/ or functional inactivation of different PP2A subunits and, therefore, loss of PP2A phosphatase activity towards certain substrates. Likewise, impaired PP2A phosphatase activity has been linked to B-cell chronic lymphocytic leukemia, Philadelphia-chromosome positive acute lymphoblastic leukemia and blast crisis chronic myeloid leukemia (CML). In CML the deregulated tyrosine kinase activity of p210-BCR/ABL oncoproteins is sufficient to induce and sustain the leukemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukemia stem cell is also resistant to imatinib. We have recently reported that the phosphatase activity of PP2A is markedly inhibited in blast crisis and, to a lesser extent, chronic phase CML patient cells and that pharmacologic re-activation of PP2A phosphatase activity by activating drugs such as Forskolin and FTY720 led to growth suppression, enhanced apoptosis impaired clonogenic potential and decreased in vivo leukemogenesis of imatinib-sensitive and -resistant CML-BC and CML-CP patient. Furthermore we have evidence that PP2A inactivation is an event that occurs also at the level of the leukemic stem cell and that PP2A re-activation hampers the survival and self-renewal of CML stem cells and possibly overcome the resistance of CML quiescent stem cells to tyrosine kinase inhibitor monotherapy. Thus, inducing PP2A phosphatase activity has the potential to eradicate CML by efficiently targeting both leukemic stem and progenitor cells regardless of their degree of sensitivity to kinase. Therefore, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for CML patients

Multiscale mathematical models for simulation and scale-up of green processes in the perspective of industrial sustainability

The present work presents research studies aimed at developing tools useful to design engineering solutions moving in the direction of industrial sustainability. The investigations hereinafter discussed regard an extraction process of active compounds \u2013 polyphenols \u2013 from agro-food industry wastes (olive and grape pomaces) and a biorefinery exploiting waste frying oil, solid organic wastes and algal biomass to produce biofuels. In particular, for the former topic, a procedure aimed at the evaluation of the technological feasibility at pilot scale of said process is discussed. The proposed approach takes into consideration the extended kinetic route coupled with mathematical simulation. Detailed physically-based dynamic mathematical models, taking into account mass and energy balance equations, are adopted to describe both the lab-scale and the pilot-scale reactors. Chemical physical parameters appearing in the models are estimated from the experimental data at lab-scale or are partially taken from literature. Different heating systems are designed for the pilot scale reactor and their performance is tested by simulation. Characteristic times are evaluated also during start-ups and different control loops are analyzed in order to set-up the best process and operating variables. Average yields in polyphenols are finally evaluated for both the batch and the continuous operated pilot reactor, by considering feed variability and fluctuations of process parameters. For what concerns the biorefinery, special attention was devoted to the modeling of the airlift reactor, its most delicate and complex component. In fact, to optimize this interesting microalgae cultivation system, a precise description of the moving interfaces formed by the liquid and gas phase is critical. In this study, coupled front capturing methods (standard and conservative level set methods) and finite difference method are used to simulate gas bubbles dynamics in a pilot-scale external loop air-lift photobioreactor in which microalgae are used to capture CO2 from flue gas and to treat wastewater. Numerical simulations are carried out on rectangular domains representing different sections of the vertical axis of the riser. The data employed was either acquired from previous experimental campaigns carried out in the airlift reactor or found in the literature. The rise, shape dynamics and coalescence process of the bubbles of flue gas are studied. Moreover, for each analyzed applications, a procedure based on Buckingham \u3c0-theorem to perform a rigorous scale-up is proposed. In this way, scale-invariant dimensionless groups describing and summarizing the considered processes could be identified. For the research focused on the scale-up of photobioreactors used to cultivate Chlorella Vulgaris, an experimental campaign at three levels was designed and carried out to evaluate the characteristic dimensionless numbers individuated by the theoretical formulation. Since scale-up regards both geometrical dimensions and type of reactor, passing from lab-scale stirred tanks to pilot scale tubular and airlift, particular attention was devoted to define characteristic lengths inside the dimensionless numbers

Protein phosphatase 2A as a therapeutic target in acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous malignant disorder of hematopoietic progenitor cells in which several genetic and epigenetic aberrations have been described. Despite progressive advances in our understanding of the molecular biology of this disease, the outcome for most patients is poor. It is therefore necessary to develop more effective treatment strategies. Genetic aberrations affecting kinases have been widely studied in AML; however, the role of phosphatases remains underexplored. Inactivation of the tumor suppressor protein phosphatase 2A (PP2A) is frequent in AML patients, making it a promising target for therapy. There are several PP2A inactivating mechanisms reported in this disease. Deregulation or specific post-translational modifications of PP2A subunits have been identified as a cause of PP2A malfunction, which lead to deregulation of proliferation or apoptosis pathways, depending on the subunit affected. Likewise, overexpression of either SET or CIP2A, endogenous inhibitors of PP2A, is a recurrent event in AML that impairs PP2A activity, contributing to leukemogenesis progression. Interestingly, the anticancer activity of several PP2A-activating drugs (PADs) depends on interaction/sequestration of SET. Preclinical studies show that pharmacological restoration of PP2A activity by PADs effectively antagonizes leukemogenesis, and that these drugs have synergistic cytotoxic effects with conventional chemotherapy and kinase inhibitors, opening new possibilities for personalized treatment in AML patients, especially in cases with SET-dependent inactivation of PP2A. Here, we review the role of PP2A as a druggable tumor suppressor in AML